EP0553792B1 - Process for the preparation of the disodium salt hemiheptahydrate of ceftriaxone - Google Patents
Process for the preparation of the disodium salt hemiheptahydrate of ceftriaxone Download PDFInfo
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- EP0553792B1 EP0553792B1 EP93101216A EP93101216A EP0553792B1 EP 0553792 B1 EP0553792 B1 EP 0553792B1 EP 93101216 A EP93101216 A EP 93101216A EP 93101216 A EP93101216 A EP 93101216A EP 0553792 B1 EP0553792 B1 EP 0553792B1
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- methyl
- disodium salt
- oxo
- triazin
- hydroxy
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
Definitions
- the invention relates to a new and improved process for the preparation of ceftriaxone disodium salt hemiheptahydrate of the formula I.
- Ceftriaxone is the generic name for the 7 - ⁇ [2- (2-aminothiazol-4-yl) -2- syn- methoxyimino] acetamido ⁇ -3 - ⁇ [(2,5-dihydro-6-hydroxy-2-methyl -5-oxo- as- triazin-3-yl) thio] methyl ⁇ -3-cephem-4-carboxylic acid.
- the compound is a third generation semisynthetic cephalosporin antibiotic and is used in the form of the disodium salt hemiheptahydrate for parenteral use in the treatment of severe infections such as acute and chronic infections of the urinary tract, respiratory infections, endocarditis, meningitis and the like. used.
- the invention further relates to 7-amino-3 - ⁇ [2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio] methyl ⁇ -3-cephem-4- carboxylic acid disodium salt with the following formula II:
- This new intermediate is by quantitative neutralization of the 7-amino-3 - ⁇ [2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio] methyl ⁇ -3-cephem -4-carboxylic acid in the form of the free acid with an aqueous NaHCO 3 solution.
- EP-B-0005830 describes new derivatives of 7- [2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido] cephalosporanic acid of the general formula wherein X is a 2,5-dihydro-6-hydroxy-2-methyl-5-oxo- as- triazin-3-yl group or its corresponding tautomeric form, the 1,2,5,6-tetrahydro-2- methyl-5,6-dioxo- as- triazin-3-yl group according to the following structure means, and esters / ethers and salts of this compound and their hydrates are described and claimed, the compounds of the above formula being present in the syn-isomeric or in the anti-isomeric form or as mixtures of these two forms.
- the preferred products are the (6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2- (Z-methoxyimino) acetamido] -3 - ⁇ [(2,5-dihydro-6-hydroxy -2-methyl-5-oxo- as- triazin-3-yl) thio] -methyl) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid and their Salts and the corresponding hydrates or hydrates of the salts claimed in EP-B-5830.
- Ceftriaxone is a valuable cefalosporin antibiotic with a broad spectrum of activity against Gram-positive and Gram-negative microorganisms including ⁇ -lactamase-forming staphylococci and various ⁇ -lactamase-forming Gram-negative bacteria such as Pseudomonas aeruginosa, Haemophilus influenzae, Serscheroteia cola, Escherichia coli, Escherichia coli - and Klebsiella genera .
- the manufacturing process is based on known methods for the production of structure-like compounds described in DE-A-2527291 and in equivalent US-A-4 091 211.
- ceftriaxone according to the process described in EP-B-0005830 is based on the cleavage of the protective group from its precursor, ie from the compound of the formula where X has the meaning given above (keto-enolic tautomerism), R is an easily removable protective group such as a trityl or chloroacetyl group and carboxy group can also be protected if necessary, and subsequent reaction of ceftriaxone to its salts or hydrates or hydrates of its salts.
- Mono- or disalts of ceftriaxone can be prepared, the formation of the disalz on the hydroxyl group of the enol form, ie the 2,5-dihydro-6-hydroxy-2-methyl-5-oxo- as- triazin-3-yl- group, can be done.
- alkali and alkaline earth salts as well as salts with organic bases such as mono- and diamines.
- the production the hydrates usually take place automatically in the course of the manufacturing process or as a result of the hygroscopic properties of the initially anhydrous product.
- the lyophilizate of the ceftriaxone disodium salt be produced, which is filled into ampoules. Before use, the lyophilisate mixed with a 2% aqueous lidocaine hydrochloride solution.
- the syn / anti mixture of the desired compound obtained can be separated in a conventional manner, such as by recrystallization or by chromatographic methods using a suitable solvent or solvent mixture.
- ceftriaxone as carboxylic acid
- acylating agents ie 2- (2-aminothiazol-4-yl) -2- syn- methoxyiminoacetic acid derivatives, which are present in the syn isomeric form with great purity, the syn configuration being retained in all stages of the reaction, including in the acylation stage.
- the 7-amino-3- (2,5-dihydro-2-methyl-6-hydroxy-5-oxo- as- triazin-3-yl) thiomethyl-3-cephem-4-carboxylic acid in which the carboxy group is protected by a trimethylsilyl group, with the new activated ester, ie with the 2- (2-aminothiazol-4-yl) -2- syn- methoxyiminoacetic acid-2-benzothiazolyl thioester, acylated.
- the starting component which is very difficult to dissolve per se, is increased and also takes place because of the hygroscopic properties of the silylation compound Acylation in an anhydrous medium and in an inert atmosphere.
- ceftriaxone disodium salt was yield (85%) by reacting the Ceftriaxons (in the form of free acid) with sodium 2-ethylhexanoate on one relatively time consuming manner as described in EP-B-0005830 is to be manufactured.
- EP-A-0399094 describes an improved process for the preparation of cefine sodium salt hemiheptahydrate, according to which 7-amino-3 - ⁇ [(2,5-dihydro-2-methyl-6-hydroxy-5-oxo- as- triazine -3-yl) thio] methyl) -3-cephem-4-carboxylic acid in aqueous solution and a suitable solvent in the presence of an amine selected from a group consisting of trimethylamine, triethylamine, 1,4-dimethyl-piperazine, N- ethylpiperidine, pyridine and dimethylaminopyridine, with 2- (2-aminothiazol-4-yl) - syn- methoxy-iminoacetic acid-2-benzothiazolyl-thioester is reacted.
- an amine selected from a group consisting of trimethylamine, triethylamine, 1,4-dimethyl-piperazine, N- ethylpipe
- the resulting aqueous solution of the salt formed is then, without isolation, treated with a suitable salt of a base selected from a group consisting of dicyclohexylamine, diphenylamine, diisopropylamine, N-terc.-butylcyclohexylamine and N, N-dibenzylethylenediamine, and the resulting one Precipitation is reacted in a suitable solvent with sodium 2-ethylhexanoate to the desired compound. A yield of approximately 85% is reported.
- the invention is based, ceftriaxone disodium salt hemiheptahydrate the task to manufacture in a new, improved and technologically feasible way, where you get the desired substance with a high overall yield and maintains high purity.
- Implementation of the individual Steps should be in aqueous medium at about room temperature and pass within a short time.
- the disodium salt obtained is then, without being isolated from the aqueous solution, with a reactive 2- (2-aminothiazol-4-yl) -2- syn- methoxy-iminoacetic acid derivative such as 2- (2-aminothiazol-4-yl ) -2- syn- methoxy-iminoacetic acid-2-benzothiazolyl-thioester in a suitable inert organic solvent such as acetone, acylated at a temperature between 0 ° C and 40 ° C, preferably at about room temperature (approx. 20-28 ° C) , and ceftriaxone disodium salt hemiheptahydrate is then isolated in a very pure form and high overall yield.
- a reactive 2- (2-aminothiazol-4-yl) -2- syn- methoxy-iminoacetic acid derivative such as 2- (2-aminothiazol-4-yl ) -2- syn- methoxy-iminoacetic acid-2-
- the solubility of the starting compound, 7-amino-3 - ⁇ [(2,5-dihydro-6-hydroxy-2-methyl-5-oxo- as- triazin-3-yl) thio] methyl ⁇ -3-cephem-4 -carboxylic acid is easily achieved by quantitative neutralization with sodium hydrogen carbonate in aqueous solution, thereby avoiding the time-consuming preparation of the ceftriaxone disodium salt in the last stage and the use of the more expensive sodium 2-ethylhexanoate.
- reaction mixture After stirring for 4 hours at room temperature, the reaction mixture was filtered. Acetate (7 ml) was added to the filtrate until cloudy, placed in the freezer for 1 hour (where a precipitate formed), then added again with 10 ml of acetone, and the resulting reaction mixture was left in the freezer overnight. A further 25 ml of acetone were then added, the mixture was cooled again in the freezer, the precipitated product was filtered off and dried under vacuum at room temperature.
Description
Die Erfindung
betrifft ein neues und verbessertes Verfahren zur Herstellung von Ceftriaxondinatriumsalz-hemiheptahydrat
der Formel I
Die Erfindung betrifft weiterhin 7-Amino-3-{[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]-methyl}-3-cephem-4-carbonsäure-dinatriumsalz
mit der folgenden Formel II:
Dieses neue Zwischenprodukt wird durch quantitative Neutralisation der 7-Amino-3-{[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl}-3-cephem-4-carbonsäure in Form der freien Säure mit einer wäßrigen NaHCO3-Lösung hergestellt.This new intermediate is by quantitative neutralization of the 7-amino-3 - {[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio] methyl} -3-cephem -4-carboxylic acid in the form of the free acid with an aqueous NaHCO 3 solution.
In EP-B-0005830 werden neue Derivate der 7-[2-(2-Amino-4-thiazolyl)-2-(methoxyimino)-acetamido]-cephalosporansäure
der allgemeinen Formel
Als bevorzugte Produkte werden die (6R,7R)-7-[2-(2-Amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-{[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]-methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carbonsäure und deren Salze sowie die entsprechenden Hydrate bzw. Hydrate der Salze in der EP-B-5830 beansprucht.The preferred products are the (6R, 7R) -7- [2- (2-amino-4-thiazolyl) -2- (Z-methoxyimino) acetamido] -3 - {[(2,5-dihydro-6-hydroxy -2-methyl-5-oxo- as- triazin-3-yl) thio] -methyl) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid and their Salts and the corresponding hydrates or hydrates of the salts claimed in EP-B-5830.
Diese Verbindung ist jetzt unter der generischen Bezeichnung Ceftriaxon bekannt. Ceftriaxon ist ein wertvolles Cefalosporin-Antibiotikum mit breitem Wirkungsspektrum gegen Gram-positive sowie Gram-negative Mikroorganismen einschliesslich β-Laktamase bildender Staphylokokken und verschiedener β-Laktamase bildender Gram-negativer Bakterien wie z.B. Pseudomonas aeruginosa, Haemophilus influenzae, Escherichia coli, Serratia marascens, Proteus- und Klebsiella-Gattungen.This compound is now known under the generic name of ceftriaxone. Ceftriaxone is a valuable cefalosporin antibiotic with a broad spectrum of activity against Gram-positive and Gram-negative microorganisms including β-lactamase-forming staphylococci and various β-lactamase-forming Gram-negative bacteria such as Pseudomonas aeruginosa, Haemophilus influenzae, Serscheroteia cola, Escherichia coli, Escherichia coli - and Klebsiella genera .
Das Herstellungsverfahren beruht auf bekannten Methoden zur Herstellung von strukturähnlichen Verbindungen, beschrieben in der DE-A-2527291 bzw. in der äquivalenten US-A-4 091 211.The manufacturing process is based on known methods for the production of structure-like compounds described in DE-A-2527291 and in equivalent US-A-4 091 211.
Die Synthese von Ceftriaxon gemäss dem in EP-B-0005830 beschriebenen Verfahren
beruht auf der Abspaltung der Schutzgruppe aus dessen Precursor, d.h. aus der Verbindung
der Formel
Es können Mono- oder Disalze des Ceftriaxons hergestellt werden, wobei die Bildung des Disalzes an der Hydroxygruppe der Enolform, d.h. der 2,5-Dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl-gruppe, erfolgen kann.Mono- or disalts of ceftriaxone can be prepared, the formation of the disalz on the hydroxyl group of the enol form, ie the 2,5-dihydro-6-hydroxy-2-methyl-5-oxo- as- triazin-3-yl- group, can be done.
Es wird die Möglichkeit der Herstellung von Alkali- und Erdalkalisalzen sowie Salzen mit organischen Basen wie Mono- und Diaminen beschrieben. Die Herstellung der Hydrate erfolgt zumeist automatisch im Zuge des Herstellungsverfahrens oder als Folge der hygroskopischen Eigenschaften des zunächst wasserfreien Produkts.There will be the possibility of producing alkali and alkaline earth salts as well as salts with organic bases such as mono- and diamines. The production the hydrates usually take place automatically in the course of the manufacturing process or as a result of the hygroscopic properties of the initially anhydrous product.
Für parenterale Zubereitungen kann das Lyophilisat des Ceftriaxon-dinatrumsalzes hergestellt werden, das in Ampullen abgefüllt wird. Vor Gebrauch wird das Lyophilisat mit einer 2%-igen wäßrigen Lidocainhydrochlorid-Lösung versetzt.For parenteral preparations, the lyophilizate of the ceftriaxone disodium salt be produced, which is filled into ampoules. Before use, the lyophilisate mixed with a 2% aqueous lidocaine hydrochloride solution.
Gemäss dem in EP-B-0005830 beschriebenen Verfahren kann das erhaltene syn/anti-Gemisch der gewünschten Verbindung auf übliche Weise wie durch Umkristallisation oder durch chromatographische Methoden unter Verwendung eines geeigneten Lösungsmittels bzw. Lösungsmittelgemisches aufgetrennt werden.According to the process described in EP-B-0005830, the syn / anti mixture of the desired compound obtained can be separated in a conventional manner, such as by recrystallization or by chromatographic methods using a suitable solvent or solvent mixture.
In der einschlägigen Literatur sind noch einige verbesserte Verfahren zur Synthese von Ceftriaxon (als Carbonsäure) beschrieben, die auf der Auswahl von neuen und verbesserten Acylierungsmitteln, d.h. 2-(2-Aminothiazol-4-yl)-2-syn-methoxyiminoessigsäure-Derivaten, die in der syn-isomeren Form mit grosser Reinheit vorliegen, wobei die syn-Konfiguration in allen Stufen der Umsetzung, auch in der Acylierungsstufe erhalten bleibt, beruhen.The relevant literature also describes some improved processes for the synthesis of ceftriaxone (as carboxylic acid) which are based on the selection of new and improved acylating agents, ie 2- (2-aminothiazol-4-yl) -2- syn- methoxyiminoacetic acid derivatives, which are present in the syn isomeric form with great purity, the syn configuration being retained in all stages of the reaction, including in the acylation stage.
Bei den vorbekannten reaktionsfähigen Derivaten, besonders bei den aktivierten Estern, kann es während der Umsetzung wegen der einigermassen unstabilen syn-Konfiguration zu einem erhöhten Anteil an anti-Isomeren und dadurch zu einer geringeren Ausbeute am gewünschen syn-Isomer kommen.In the case of the known reactive derivatives, particularly the activated esters, an increased proportion of anti- isomers and thus a lower yield of the desired syn isomer can occur during the reaction because of the somewhat unstable syn configuration.
Bei Verwendung verbesserter Acylierungsmittel mit syn-Konfiguration bleibt diese bei der Umsetzung erhalten und die gewünschte Substanz (Ceftriaxon) wird in grosser Reinheit und Ausbeute erhalten; darüberhinaus besteht kein Bedürfnis nach dem Schutz des Amino-Substituenten im Tiazolylring der Seitenkette, wie in der EP-A-0175814, DE-A-37 20 681 oder in EP-A-0037380 bzw. ihrem Äquivalent US-A-4 767 852 beschrieben ist. Gemäss dem letztgenannten Verfahren wird die 7-Amino-3-(2,5-dihydro-2-methyl-6-hydroxy-5-oxo-as-triazin-3-yl)thiomethyl-3-cephem-4-carbonsäure, worin die Carboxygruppe durch eine Trimethylsilylgruppe geschützt ist, mit dem neuen aktivierten Ester, d.h. mit dem 2-(2-Aminothiazol-4-yl)-2-syn-methoxyiminoessigsäure-2-benzthiazolyl-thioester, acyliert.If improved acylating agents with syn configuration are used, this is retained during the reaction and the desired substance (ceftriaxone) is obtained in great purity and yield; furthermore, there is no need for protecting the amino substituent in the tiazolyl ring of the side chain, as in EP-A-0175814, DE-A-37 20 681 or in EP-A-0037380 or its equivalent US Pat. No. 4,767,852 is described. According to the latter method, the 7-amino-3- (2,5-dihydro-2-methyl-6-hydroxy-5-oxo- as- triazin-3-yl) thiomethyl-3-cephem-4-carboxylic acid, in which the carboxy group is protected by a trimethylsilyl group, with the new activated ester, ie with the 2- (2-aminothiazol-4-yl) -2- syn- methoxyiminoacetic acid-2-benzothiazolyl thioester, acylated.
Durch den Schutz der Carboxygruppe mit dem Silylierungsmittel wird die Löslichkeit der an sich sehr schwer löslichen Ausgangskomponente erhöht und ausserdem erfolgt wegen der hygroskopischen Eigenschaften der Silylierungsverbindung die Acylierung in einem wasserfreien Medium und in einer inerten Atmosphäre.By protecting the carboxy group with the silylating agent, solubility is reduced the starting component, which is very difficult to dissolve per se, is increased and also takes place because of the hygroscopic properties of the silylation compound Acylation in an anhydrous medium and in an inert atmosphere.
Nach erfolgter Acylierung und Isolation des Ceftriaxons in reiner Form und hoher Ausbeute (85%) konnte das Ceftriaxon-dinatriumsalz durch Umsetzung des Ceftriaxons (in Form von freier Säure) mit Natrium-2-ethylhexanoat auf eine verhältnismässig zeitraubende Weise wie in der EP-B-0005830 beschrieben ist, hergestellt werden.After acylation and isolation of the ceftriaxone in pure form and high The ceftriaxone disodium salt was yield (85%) by reacting the Ceftriaxons (in the form of free acid) with sodium 2-ethylhexanoate on one relatively time consuming manner as described in EP-B-0005830 is to be manufactured.
In der EP-A-0399094 wird ein verbessertes Verfahren zur Herstellung von Cefdinatriumsalz-hemiheptahydrat beschrieben,wonach 7-Amino-3-{[(2,5-dihydro-2-methyl-6-hydroxy-5-oxo-as-triazin-3-yl)thio]methyl)-3-cephem-4-carbonsäure in wäßriger Lösung und einem geeigneten Lösungsmittel in Anwesenheit eines Amins, ausgewählt aus einer Gruppe, bestehend aus Trimethylamin, Triethylamin, 1,4-Dimethyl-piperazin, N-ethylpiperidin, Pyridin und Dimethylaminopyridin, mit 2-(2-Aminothiazol-4-yl)-syn-methoxy-iminoessigsäure-2-benzothiazolyl-thioester umgesetzt wird. Die erhaltene wäßrige Lösung des entstandenen Salzes wird anschliessend, ohne Isolierung, mit einem geeigneten Salz einer Base, ausgewählt aus einer Gruppe bestehend aus Dicyclohexylamin, Diphenylamin, Diisopropylamin, N-terc.-Butylcyclohexylamin und N,N-Dibenzylethylendiamin, behandelt, und der erhaltene Niederschlag wird in einem.geeigneten Lösungsmittel mit Natrium-2-ethylhexanoat zur gewünschten Verbindung umgesetzt. Es wird eine Ausbeute von etwa 85% angegeben.EP-A-0399094 describes an improved process for the preparation of cefine sodium salt hemiheptahydrate, according to which 7-amino-3 - {[(2,5-dihydro-2-methyl-6-hydroxy-5-oxo- as- triazine -3-yl) thio] methyl) -3-cephem-4-carboxylic acid in aqueous solution and a suitable solvent in the presence of an amine selected from a group consisting of trimethylamine, triethylamine, 1,4-dimethyl-piperazine, N- ethylpiperidine, pyridine and dimethylaminopyridine, with 2- (2-aminothiazol-4-yl) - syn- methoxy-iminoacetic acid-2-benzothiazolyl-thioester is reacted. The resulting aqueous solution of the salt formed is then, without isolation, treated with a suitable salt of a base selected from a group consisting of dicyclohexylamine, diphenylamine, diisopropylamine, N-terc.-butylcyclohexylamine and N, N-dibenzylethylenediamine, and the resulting one Precipitation is reacted in a suitable solvent with sodium 2-ethylhexanoate to the desired compound. A yield of approximately 85% is reported.
Bei diesem Verfahren wurde die Löslichkeit der schwerlöslichen Ausgangskomponente dadurch erhöht, dass deren Amin- bzw. Triethylaminsalz hergestellt wurde, was gleichzeitig auch den Schutz der Carboxygruppe zur Folge hatte. Allerdings ist es bei dieser Umsetzung ungünstig, dass einige sekundäre Amine und deren Salze, wie z.B. N,N-Dibenzylethylendiamin-diacetat, für die weitere Verwendung gesondert hergestellt werden müssen. Durch diese zeitraubende Herstellung der Zwischenprodukte (Umsetzungsreagentien) wird die ansonsten sehr hohe Gesamtausbeute herabgesetzt.In this process, the solubility of the poorly soluble starting component increased by producing their amine or triethylamine salt, which also resulted in the protection of the carboxy group. However it is unfavorable in this implementation that some secondary amines and their salts, such as e.g. N, N-dibenzylethylenediamine diacetate, separately for further use have to be manufactured. Through this time-consuming production of the intermediate products (Reaction reagents) becomes the otherwise very high overall yield reduced.
Der Erfindung liegt die Aufgabe zugrunde, Ceftriaxon-dinatriumsalz-hemiheptahydrat auf eine neue, verbesserte und technologisch leicht durchführbare Weise herzustellen, bei der man die gewünschte Substanz mit einer hohen Gesamtausbeute und einer hohen Reinheit erhält. Die Umsetzung der einzelnen Stufen soll in wäßrigem Medium bei etwa Raumtemperatur und innerhalb kurzer Zeit verlaufen.The invention is based, ceftriaxone disodium salt hemiheptahydrate the task to manufacture in a new, improved and technologically feasible way, where you get the desired substance with a high overall yield and maintains high purity. Implementation of the individual Steps should be in aqueous medium at about room temperature and pass within a short time.
Diese Aufgabe wird durch das in Patentanspruch 1 angegebene Verfahren sowie durch das neue Zwischenprodukt 7-Amino-3-{[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]-methyl}-3-cephem-4-carbonsäure-dinatriumsalz gelöst. This object is achieved by that specified in claim 1 Process and by the new intermediate 7-amino-3 - {[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thio] methyl} -3-cephem -4-carboxylic acid disodium salt solved.
Erfindungsgemäß stellt man zuerst einfach durch quantitative
Neutralisation der 7-Amino-3-{[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl}-3-cephem-4-carbonsäure
in Form der freien Säure mit einer
wäßrigen Natriumhydrogencarbonatlösung das Dinatriumsalz dieser Säure der Formel
II
Die Löslichkeit der Ausgangsverbindung, 7-Amino-3-{[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl}-3-cephem-4-carbonsäure, wird auf einfache Weise durch quantitative Neutralisation mit Natriumhydrogencarbonat in wäßriger Lösung erzielt, wodurch die zeitraubende Herstellung des Ceftriaxondinatriumsalzes in der letzten Stufe und die Verwendung des teureren Natrium-2-ethylhexanoats vermieden wird.The solubility of the starting compound, 7-amino-3 - {[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo- as- triazin-3-yl) thio] methyl} -3-cephem-4 -carboxylic acid, is easily achieved by quantitative neutralization with sodium hydrogen carbonate in aqueous solution, thereby avoiding the time-consuming preparation of the ceftriaxone disodium salt in the last stage and the use of the more expensive sodium 2-ethylhexanoate.
Ausserdem entfällt der Schutz der Carboxygruppe in der Ausgangsverbindung, wie er in der oben angeführten Patentliteratur, z.B. in EP-A-0037380, beschrieben wird.In addition, the protection of the carboxy group in the starting compound, such as he in the patent literature cited above, e.g. in EP-A-0037380.
Als Acylierungsmittel kann das aus der Literatur bekannte und dann beschriebene reaktive 2-(2-Aminothiazol-4-yl)-2-syn-methoxyiminoessigsäure-Derivat, vorzugsweise ihr 2-Benzothiazolyl-thioester, eingesetzt werden, da es die vollständige Kontrolle der Geometrie der -C=N-syn-Konfiguration und dadurch eine hohe Ausbeute an syn-Isomeren der gewünschten Verbindung gewährleistet.The reactive 2- (2-aminothiazol-4-yl) -2- syn- methoxyiminoacetic acid derivative, preferably its 2-benzothiazolyl thioester, known from the literature and then described, can be used as the acylating agent, since it gives complete control of the geometry the -C = N- syn configuration and thereby ensures a high yield of syn isomers of the desired compound.
Der Reaktionsverlauf, die Identifizierung und der Gehalt an der gewünschten Verbindung wurden mittels Hochleistungs-Flüssigkeits-Chromatographie -Chromatographie (HPLC) auf schwach basischem Ionenaustauscher (Lichosorb-NH2) mit einem Phosphatpuffer/ Acetonitril-Gemisch als mobile Phase und UV-Detektion bei 270 nm festgestellt. Die Reinheit der gewünschten Verbindung war hoch und mit der authentischen Probe vergleichbar.The course of the reaction, the identification and the content of the desired compound were determined using high-performance liquid chromatography-chromatography (HPLC) on weakly basic ion exchanger (Lichosorb-NH 2 ) with a phosphate buffer / acetonitrile mixture as mobile phase and UV detection at 270 nm found. The purity of the desired compound was high and comparable to the authentic sample.
Die Erfindung wird durch das folgende, in keiner Weise einschränkende Beispiel näher erläutert.The invention is illustrated by the following non-limiting example explained in more detail.
200 mg (0,539 mMol) 7-Amino-3-{[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl}-3-cephem-4-carbonsäure
wurden in 4,5 ml Wasser suspendiert,
mit 92 mg Natriumhydrogencarbonat (NaHCO3) versetzt, und die Suspension
wurde bis zur Klärung gerührt. Mit der erhaltenen Lösung wurde dann unter
Rühren eine gesondert hergestellte Lösung von 230 mg (0,656 mMol) 2-(2-Aminothiazol-4-yl)-2-syn-methoxyiminoessigsäure-2-benzothiazolyl-thioester
in 9 ml
Aceton versetzt. Nach 4-stündigem Rühren bei Raumtemperatur wurde das
Reaktionsgemisch filtriert. Das Filtrat wurde mit Aceton (7 ml) bis zur Trübheit versetzt,
für 1 Stunde in den Gefrierschrank gestellt (wobei sich ein Niederschlag
bildete), dann abermals mit 10 ml Aceton versetzt, und das erhaltene Reaktionsgemisch
wurde über Nacht im Gefrierschrank stehengelassen. Danach wurde es
mit weiteren 25 ml Aceton versetzt, erneut im Gefrierschrank abgekühlt, das ausgeschiedene
Produkt wurde abgefiltert und unter Vakuum bei Raumtemperatur
getrocknet. Es wurden 325 mg (91%) 7-{[2-(2-Aminothiazol-4-yl)-2-syn-methoxyimino]acetamido}-3-{[(2,5-di-hydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)-thio]methyl}-3-cephem-4-carbon-säure-dinatriumsalz-hemiheptahydrat
(Ceftriaxon-dinatriumsalz-hemiheptahydrat)
von hoher Reinheit erhalten. Die analytischen
Parameter waren mit denen der authentischen Probe identisch.
1H NMR-Spektrum (DMSO) (δ, ppm)
6,76 5-Thiazolyl (1H, s)
3,83 -OCH3 (3H, s)
3,42 -NCH3 (3H, s)200 mg (0.539 mmol) 7-amino-3 - {[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo- as- triazin-3-yl) thio] methyl} -3-cephem- 4-carboxylic acid was suspended in 4.5 ml of water, 92 mg of sodium hydrogen carbonate (NaHCO 3 ) were added, and the suspension was stirred until clarification. A separately prepared solution of 230 mg (0.656 mmol) of 2- (2-aminothiazol-4-yl) -2- syn- methoxyiminoacetic acid-2-benzothiazolyl-thioester in 9 ml of acetone was then added to the resulting solution with stirring. After stirring for 4 hours at room temperature, the reaction mixture was filtered. Acetate (7 ml) was added to the filtrate until cloudy, placed in the freezer for 1 hour (where a precipitate formed), then added again with 10 ml of acetone, and the resulting reaction mixture was left in the freezer overnight. A further 25 ml of acetone were then added, the mixture was cooled again in the freezer, the precipitated product was filtered off and dried under vacuum at room temperature. 325 mg (91%) of 7 - {[2- (2-aminothiazol-4-yl) -2- syn- methoxyimino] acetamido} -3 - {[(2,5-di-hydro-6-hydroxy- 2-methyl-5-oxo- as- triazin-3-yl) thio] methyl} -3-cephem-4-carboxylic acid disodium salt hemiheptahydrate (ceftriaxone disodium salt hemiheptahydrate) of high purity. The analytical parameters were identical to those of the authentic sample.
1 H NMR spectrum (DMSO) (δ, ppm)
6.76 5-thiazolyl (1H, s)
3.83 -OCH 3 (3H, s)
3.42 -NCH 3 (3H, s)
500 mg (1,35 mMol) 7-Amino-3-{[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl}-3-cephem-4-carbonsäure wurden in 10 ml Wasser suspendiert, mit 230 mg Natriumhydrogencarbonat versetzt, dann mit 100 ml Aceton gefällt, und das erhaltene harzartige Produkt wurde über Nacht im Gefrierschrank stehengelassen, dann abgefiltert und in 30 ml Aceton suspendiert Nach einstündigem Rühren wurde das Produkt abgefiltert und in Vakuum bei 40 °C getrocknet. Es wurde 7-Amino-3-{[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl}-3-cephem-4-carbonsäure-dinatriumsalz in der Form eines pulverigen, hellgelben Produktes, das bei einer Temperatur über 200 °C schmilzt, erhalten.500 mg (1.35 mmol) 7-amino-3 - {[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo- as- triazin-3-yl) thio] methyl} -3- cephem-4-carboxylic acid was suspended in 10 ml of water, 230 mg of sodium hydrogen carbonate was added, then precipitated with 100 ml of acetone, and the resinous product obtained was left to stand in the freezer overnight, then filtered off and suspended in 30 ml of acetone. After stirring for 1 hour, the Filtered product and dried in vacuum at 40 ° C. 7-Amino-3 - {[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo- as- triazin-3-yl) thio] methyl} -3-cephem-4-carboxylic acid was disodium salt in the form of a powdery, light yellow product that melts at a temperature above 200 ° C.
Claims (6)
- A process for the preparation of 7-{[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino]acetamido}-3-{[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl}-3-cephem-4-carboxylic acid disodium salt hemiheptahydrate (ceftriaxon disodium salt hemiheptahydrate) of formula Icharacterized in that 7-amino-3-{[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)-thio]-methyl}-3-cephem-4-carboxylic acid is reacted with sodium hydrogen carbonate in an aqueous medium to 7-amino-3-{[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl}-3-cephem-4-carboxylic acid disodium salt of formula II
and then, without isolation from an aqueous medium, it is acylated with a reactive 2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetic acid derivative of formula III
in a suitable inert organic solvent at a temperature between 0 °C and 40 °C and then ceftriaxon disodium salt hemiheptahydrate is isolated in a pure form.
- A process according to claim 1, characterized in that the reaction is carried out at room temperature.
- A process according to any of claims 1 or 2, characterized in that 2-(2-aminothiazol-4-yl)-2-syn-metoxyimino acetic acid-2-benzothiazolyl-thioester is used as the reactive acylating derivative.
- A process according to any of previous claims 1 to 3, characterized in that acetone is used as the inert organic solvent.
- A process according to any of previous claims 1 to 4, characterized in that after the acylating step the reaction mixture is filtered, additional acetone is added to the filtrate until ceftriaxon disodium salt hemiheptahydrate of the formula I is obtained in a pure form, the latter is isolated and dried.
- 7-amino-3-{[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl}-3-cephem-4-carboxylic acid disodium salt.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT132/92 | 1992-01-28 | ||
| AT0013292A AT398764B (en) | 1992-01-28 | 1992-01-28 | METHOD FOR PRODUCING CEFTRIAXONDINATRIUM SALZHEMIHEPTAHYDRATE |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| EP0553792A2 EP0553792A2 (en) | 1993-08-04 |
| EP0553792A3 EP0553792A3 (en) | 1993-12-29 |
| EP0553792B1 true EP0553792B1 (en) | 1999-05-26 |
Family
ID=3482382
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP93101216A Expired - Lifetime EP0553792B1 (en) | 1992-01-28 | 1993-01-27 | Process for the preparation of the disodium salt hemiheptahydrate of ceftriaxone |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US5527906A (en) |
| EP (1) | EP0553792B1 (en) |
| KR (1) | KR960002911B1 (en) |
| AT (1) | AT398764B (en) |
| CA (1) | CA2088173A1 (en) |
| CZ (1) | CZ282447B6 (en) |
| DE (1) | DE59309598D1 (en) |
| DK (1) | DK0553792T3 (en) |
| ES (1) | ES2133334T3 (en) |
| PL (1) | PL172486B1 (en) |
| RU (1) | RU2081120C1 (en) |
| SI (1) | SI9300042A (en) |
| SK (1) | SK279280B6 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT399877B (en) * | 1992-02-20 | 1995-08-25 | Biochemie Gmbh | NEW METHOD FOR PRODUCING CEFTRIAXONE |
| IN184690B (en) * | 1996-03-18 | 2000-09-23 | Ranbaxy Lab Ltd | |
| KR100361829B1 (en) * | 1997-04-16 | 2005-08-17 | 주식회사 엘지생명과학 | The process for preparing a ceftriaxone from reactive organic acid derivatives |
| RU2504548C1 (en) * | 2012-09-28 | 2014-01-20 | Федеральное Государственное Автономное Образовательное Учреждение Высшего Профессионального Образования "Сибирский Федеральный Университет" (Сфу) | DERIVATIVE OF β-LACTAM CEFTRIAXONE ANTIBIOTIC |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1240314A (en) * | 1974-06-21 | 1988-08-09 | Marc Montavon | Acyl derivatives |
| DE2714880A1 (en) * | 1977-04-02 | 1978-10-26 | Hoechst Ag | CEPHEMDER DERIVATIVES AND PROCESS FOR THEIR PRODUCTION |
| MC1259A1 (en) * | 1978-05-30 | 1980-01-14 | Hoffmann La Roche | ACYL DERIVATIVES |
| CH641468A5 (en) * | 1978-05-30 | 1984-02-29 | Hoffmann La Roche | CEPHEM DERIVATIVES. |
| FI67385C (en) * | 1979-11-21 | 1985-03-11 | Hoffmann La Roche | PROCEDURE FOR FRAMSTATION OF AV (6R 7R) -7- (2- (2-AMINO-4-THIAZOLYL) -2- (Z-METHOXYIMINO) ACETAMIDO) -3-CEFEM-4-CARBOXYL SYRATER DERIVATIVES |
| DE3165922D1 (en) * | 1980-03-28 | 1984-10-18 | Biochemie Gmbh | New process for the production of cephalosporin antibiotics, and novel intermediates used in such process and their production |
| ES510270A0 (en) * | 1982-03-10 | 1983-01-16 | Servicios Y Suministros Farmac | PROCEDURE FOR THE OBTAINING OF THE DISODIC SALT OF THE ACID 7- (2- (2-AMINO-4-THIAZOLIL) -2-METOXIIMINO-ACETAMIDO) -3 - ((2,5-DIHIDRO-6-HIDROXI-2-METHYL- 5-OXO-AS-TRIAZIN-3-IL) TIO) METHYL) -8-OXO-5-TIA-1-AZABICICLO (4.2.0) OCT-2-ENE-2-CARBOXILICO |
| KR870001332B1 (en) * | 1984-09-27 | 1987-07-18 | 한미약품공업 주식회사 | Process for preparing cephem derivatives |
| KR890002107B1 (en) * | 1986-06-25 | 1989-06-19 | 재단법인 한국화학연구소 | Process for preparing cephalosporin derivatives |
| DE3911322A1 (en) * | 1989-04-07 | 1990-10-11 | Hoechst Ag | METHOD FOR PRODUCING CEFODIZIM DINATRIUM |
| IT1234385B (en) * | 1989-05-23 | 1992-05-18 | Sbd Synthetic And Biolog Devel | IMPROVED PROCEDURE FOR THE PRODUCTION OF AN ANTIBIOTIC SUBSTANCE BELONGING TO THE CEPHALOSPORINE GROUP |
-
1992
- 1992-01-28 AT AT0013292A patent/AT398764B/en not_active IP Right Cessation
-
1993
- 1993-01-26 PL PL93297535A patent/PL172486B1/en unknown
- 1993-01-27 CZ CZ9391A patent/CZ282447B6/en not_active IP Right Cessation
- 1993-01-27 US US08/009,957 patent/US5527906A/en not_active Expired - Fee Related
- 1993-01-27 DK DK93101216T patent/DK0553792T3/en not_active Application Discontinuation
- 1993-01-27 ES ES93101216T patent/ES2133334T3/en not_active Expired - Lifetime
- 1993-01-27 RU RU9393004504A patent/RU2081120C1/en active
- 1993-01-27 DE DE59309598T patent/DE59309598D1/en not_active Expired - Fee Related
- 1993-01-27 CA CA002088173A patent/CA2088173A1/en not_active Abandoned
- 1993-01-27 EP EP93101216A patent/EP0553792B1/en not_active Expired - Lifetime
- 1993-01-28 SK SK41-93A patent/SK279280B6/en unknown
- 1993-01-28 SI SI19939300042A patent/SI9300042A/en not_active IP Right Cessation
- 1993-01-28 KR KR1019930001024A patent/KR960002911B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| DK0553792T3 (en) | 1999-11-08 |
| ES2133334T3 (en) | 1999-09-16 |
| DE59309598D1 (en) | 1999-07-01 |
| EP0553792A3 (en) | 1993-12-29 |
| CZ9193A3 (en) | 1993-12-15 |
| AT398764B (en) | 1995-01-25 |
| ATA13292A (en) | 1994-06-15 |
| KR930016427A (en) | 1993-08-26 |
| PL297535A1 (en) | 1993-10-04 |
| CZ282447B6 (en) | 1997-07-16 |
| US5527906A (en) | 1996-06-18 |
| KR960002911B1 (en) | 1996-02-28 |
| EP0553792A2 (en) | 1993-08-04 |
| RU2081120C1 (en) | 1997-06-10 |
| SK279280B6 (en) | 1998-09-09 |
| SI9300042A (en) | 1993-09-30 |
| CA2088173A1 (en) | 1993-07-29 |
| PL172486B1 (en) | 1997-09-30 |
| SK4193A3 (en) | 1993-09-09 |
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